This Program Project Grant (PPG) competitive renewal application seeks to build on its success of the past four years. We will continue to probe the modes of action of unique natural products showing promising anticancer activity, thereby fostering efforts to move such molecules towards clinical testing. The application further seeks to discover and characterize synthetic compounds that selectively agonize or antagonize biological pathways relevant to human cancer. Four interrelated projects are proposed. The first will employ the tools of biochemistry, molecular biology and genetics to uncover the molecular targets of natural products showing potent and selective cytotoxic activity. The second project seeks to resolve the enigmatic involvement of ornthine amino transferase (OAT) in the spindle assembly pathway of transformed cells, and further validate this molecular target for the development of anti-cancer drugs. The third project outlines a comprehensive series of experiments aimed at determining the basis for single agent toxicity of a synthetic mimic of Smac on tumor necrosis factor-secreting cancer cells. The fourth project seeks to identify and validate synthetic organic chemicals capable of either activating or inhibiting the hypoxia response pathway as a means of treating either anemia or cancer. All four programs will enlist the combined use of chemical, biochemical, genetic and molecular biological research. Each of the four projects will further rely on three technology cores sophisticated in the use of 1) high throughput screening (HTS Core), 2) small animal pharmacology (Pharmacology Core), and 3) chemical synthesis for the purposes of structure-activity relationship (SAR) studies, compound re-supply and drug formulation (Chemistry Core). All three technology cores are unique to our PPG team in the context of the sponsoring institution (UT Southwestern Medical Center), and are vital to the goals of the proposed research. Beyond serving as financial support crucial for the proposed research objectives, continued funding of this PPG is vital for sustained scientific synergy at the interfaces of chemical, biochemical, molecular biological and biophysical research at the host institution. [unreadable] [unreadable] [unreadable] [unreadable]